LC3相关的吞噬作用（LAP）对矽肺发展过程中矽尘诱发自身免疫性疾病的作用机制研究

In China, silicosis is the most severe and harmful occupational disease. Silicosis patients often develop autoimmune diseases such as systemic lupus erythematosus, rheumatic arthritis, etc. In the course of the silicosis, silica dust also triggers autoimmune response. Studies have shown that silica dust can cause abnormal immune cell apoptosis, and eventually lead to autoimmune diseases. Recently, it has been found that LC3-associated phagocytosis (LAP) plays an important role in the clearance apoptotic cells. LAP is the process that phagocytes mainly recognize and engulf of apoptotic cells through the PtdSer receptor and the specific protein Rubbicon, NOX2 is involved in degradation of apoptotic cells. LAP plays an important role in the pathogenesis of autoimmune diseases. Nevertheless, the role and mechanism of LAP in silica-induced autoimmune diseases during the development of silicosis are unclear. By observations and studies on silicosis patients, silicosis patients with autoimmune diseases and experimental silicosis models in C57BL/6 mice and lupus-prone MRL/lpr mice, the aim of our project is to illustrate the role and mechanism of LAP in silica-induced autoimmune diseases during the development of silicosis at both cellular and molecular levels. An understanding the role of LAP will provide better insight into design of novel approaches to prevent and control silicosis and silica-induced autoimmune diseases.

在我国，矽肺是尘肺中危害最严重的一种职业病。矽肺患者常伴发系统性红斑狼疮、类风湿性关节炎等自身免疫性疾病。矽尘在引起矽肺的过程中，也诱发了机体的自身免疫反应。研究表明矽尘可引起机体免疫细胞凋亡异常，最终引起自身免疫性疾病的发生。新近研究发现LC3相关的吞噬作用（LAP）是清除体内凋亡细胞的一个重要途径。LAP主要通过吞噬细胞上PtdSer等受体分子对凋亡细胞进行识别和吞噬，再通过胞内特异性蛋白Rubbicon，NOX2的参与降解和清除凋亡细胞，这一过程在自身免疫性疾病的发病中发挥重要作用。LAP在矽尘诱发自身免疫性疾病的作用机制尚不清楚。本研究拟以矽肺和矽肺合并自身免疫性疾病患者和实验性C57BL/6和狼疮倾向MRL/lpr小鼠为研究对象，在人群和实验动物中深入探明LAP在矽肺发展过程中对矽尘诱发自身免疫性疾病的作用和相关分子机制,旨在为疾病的预防和控制提供新的理论基础和实验依据。

在我国，矽肺是尘肺中危害最严重的一种职业病。矽肺患者常伴发系统性红斑狼疮、类风湿性关节炎等自身免疫性疾病。矽尘在引起矽肺的过程中，也诱发了机体的自身免疫反应。研究表明矽尘可引起机体免疫细胞凋亡异常，最终引起自身免疫性疾病的发生。研究发现LC3相关的吞噬作用（LAP）是清除体内凋亡细胞的一个重要途径。LAP主要通过吞噬细胞上PtdSer等受体分子对凋亡细胞进行识别和吞噬，再通过胞内特异性蛋白Rubicon，NOX2的参与降解和清除凋亡细胞，这一过程在自身免疫性疾病的发病中发挥重要作用。我们的研究发现矽尘暴露可损伤J774A.1巨噬细胞和C57BL/6小鼠肺组织LAP功能，激活UNC93B1/TLR7和UNC93B1/TLR9信号通路。薯蓣皂苷可通过抑制矽尘暴露狼疮倾向MRL/lpr小鼠机体免疫细胞凋亡，促进机体免疫细胞LAP功能，抑制UNC93B1/TLR7和UNC93B1/TLR9信号通路的活化，进而阻抑矽尘促发狼疮倾向MRL/lpr小鼠自身免疫性疾病的发生发展。我们同时在矽肺纤维化模型中探究半乳糖凝集素-3（Galectin-3）介导的上皮间充质转化（EMT）在矽肺纤维化发生发展的作用机制。研究发现Gal-3通过调控GSK-3β/β-catenin信号通路促进矽尘暴露诱导的EMT和矽肺纤维化，抑制Gal-3能够减轻矽尘暴露引起的EMT和矽肺纤维化的发生发展。该项目研究结果为矽肺及自身免疫性疾病的预防和控制提供新的理论基础和实验依据，也为相关疾病的治疗提供新的潜在治疗靶点。